The ras oncogene has been implicated in a large number of human carcinomas and is known to be present in 50% of colon and more than 90% of pancreatic cancers. Disruption of the function of the ras oncogene thus represents an important new target in the search for anti-cancer agents. The protein product from the ras oncogene is a small G-protein, p21ras, that is known to play a key role in signal transduction and cell proliferation. Recent work has shown that the enzyme Ras farnesyltransferase plays a key role in the farnesylation of Ras and its subsequent localization to the plasma membrane. Since membrane association of Ras is essential for its signaling and transforming function, Ras farnesyltransferase represents a new and important target for anti-cancer drug design. This application represents a major effort to design, synthesize and evaluate potent inhibitors of the enzyme Ras farnesyltransferase. In preliminary results we show that significant progress has been made in the development of peptidomimetic inhibitors of Ras farnesyltransferase. The best of these synthetic compounds function at 50 to 100 nM in vitro and at 25 microM in disrupting membrane association in intact cells. In the present application the Chemistry component of the NCDDG (program #1) plans to develop an accurate model of the active site of Ras farnesyltransferase, to design and synthesize non-peptide inhibitors of Ras farnesyltransferase, to develop novel molecular scaffolds that mimic the position and orientation of key residues on the CA/1 A/2X tetrapeptide, to synthesize transition state analogs of the farnesylation reaction that are potent inhibitors of the farnesyltransferase enzyme, to design mechanism based inhibitors of Ras farnesyltransferase that lead to covalent modification of the enzyme and to investigate the structural requirements of membrane permeability of the agents discovered and maximize the bioavailability of these potential anti-cancer drugs.